The present invention relates to a process for making the pharmaceutically active agent cabergoline and to intermediates useful in said process.
Cabergoline, chemically 1-[(6-allylergolin-8-β-yl)-carbonyl]-1-[3-(dimethylamino)-propyl]-3-ethylurea of the formula (1)
is a dopamine receptor agonist. It is a pharmaceutically useful compound that is indicated for the treatment of hyperprolactinemia and for the treatment of Parkinson disease. Cabergoline has been disclosed in GB 2074566 and U.S. Pat. No. 4,526,892.
A conventional process for making cabergoline was disclosed in GB 2103603 and comprises a reaction of the ergoline amide compound of formula (2) with ethyl isocyanate in an inert solvent (dioxane, benzene, toluene, cyclohexane).
The process disclosed in GB 2103603 requires the use of a large excess of the isocyanate (up to 36 molar equivalents), high temperatures (70–120° C.) and long reaction times (24–72 hours). Despite these drastic conditions, the reaction results in equilibrium, i.e. the conversion is incomplete and is accompanied with serious side reactions on the indole nitrogen, which decreases the yield and complicates product purification.
The above process was improved in a later patent EPB 593692 (U.S. Pat. No. 5,382,669). The reaction of ethyl isocyanate with the compound (2) proceeds in the presence of a metal catalyst chosen from Ib and IIb metal group salts, preferably copper salts (CuCl, CuCl2, CuBr and CuI) and of a phosphine of the formula PR6R7R8 in which R6, R7 and R8 are each, independently, an alkyl or aryl group optionally substituted by one or more substituents chosen from Cl, F, methyl and methoxy (preferably triphenylphosphine or tri-p-tolylphosphine) or of an alkyl phosphite, in a suitable solvent at a temperature 0–80° C., preferably 35–60° C. The amidic nitrogen is activated by the action of the copper catalyst. However the other nitrogen atoms, and particularly the indole nitrogen, may also be activated as well. The purpose of the phosphine/phosphite compound is to modulate the reaction, particularly to suppress the side reaction of the indole nitrogen atom. The large excess of the toxic and harmful ethyl isocyanate required by the earlier process may be decreased to 2–3 equivalents and the reaction proceeds in much milder conditions.
Despite this improvement, the process has serious drawbacks in low conversion rate (about 80%) and insufficient purity of the product; the latter being not much different from the uncatalyzed reaction (see the discussion in J. Org. Chem., 67, 7147 (2002)). The present inventors also confirm that the resulting cabergoline is contaminated with impurities and remainder of the starting material due to the incomplete conversion and low selectivity.
WO 2002/085902 relates to a further improvement of the production process. The amidic nitrogen of the starting ergoline-8.β-carboxamide (2) is first silylated by a silylation agent of general formula Y—Si (R6)(R7)(R8), preferably with trimethylsilyl triflate, under presence of an organic amine. The so obtained silylated intermediate compound then reacts with the ethyl isocyanate without the need of any activating catalyst and finally the silylated cabergoline is deprotected:

However, the cited document does not teach whether and/or how the silylated intermediates may be isolated and purified. Moreover, while the silylating agent activates the amidic nitrogen, it is not able to suppress the reactivity of the indole nitrogen. In fact, when repeating the process, the present inventors found that the silylated intermediate is very unstable (it is even not stable at ordinary conditions of TLC analysis, so that the reaction process cannot be monitored). Under disclosed conditions, the reaction was found incomplete and the product was accompanied with contaminants.
Ashford et al. (J. Org. Chem. 2002, 67, 7147–7150) studied the possibility of protecting the indole nitrogen in a variant process for making cabergoline. This scheme starts with the compound of formula (2), however it avoids the use of ethyl isocyanate. Instead, the compound (2), after its indole nitrogen has been protected by a tert.butoxycarbonyl group, reacts with phenylchloroformate to produce the compound (7)
which is then converted into cabergoline by a reaction with ethyl amine, followed by deprotection. Ashford et al. also studied the possibility to protect the indole nitrogen in the compound (2) within the above process by a silylation agent, such as TMS or TIPS. However they found out that these protective groups are too unstable in the subsequent steps.
In conclusion, there is a need to develop an alternate and/or improved process for making cabergoline from the ergoline amide of formula (2), which process can have, inter alia, improved conversion and less potential for side reactions on the indole nitrogen.